Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)

1st line – transsphenoidal pituitary adenomectomy

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ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
1st line – 

transsphenoidal pituitary adenomectomy

First-line therapy is transsphenoidal resection of the causative pituitary adenoma performed by an experienced surgeon.[26][72][115] Surgery can be done using an endoscopic or microscopic approach. Results are comparable between both techniques for microadenomas.[73] Whether there is potential incremental benefit with an endoscopic approach for macroadenomas remains unclear.[26][73]

Patients with mild cortisol excess (biochemical evidence of hypercortisolemia but no clinical signs or symptoms of Cushing syndrome) should have therapy carefully weighed because benefit of surgery has not been convincingly demonstrated.[71]

Consider – medical therapy before surgery

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
Consider – 

medical therapy before surgery

Treatment recommended for SOME patients in selected patient group

A somatostatin analog (pasireotide), a dopamine agonist (cabergoline), a steroidogenesis inhibitor (osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, etomidate), or a glucocorticoid receptor antagonist (mifepristone) is occasionally used short term for severe hypercortisolism before other therapies are undertaken.[91][92][93][94]

Somatostatin analog: pasireotide binds to a wide array of somatostatin receptors, with a much greater affinity for somatostatin receptor 5, which is predominantly expressed in corticotroph adenomas. Use of the regular-release formulation of pasireotide decreases cortisol in most patients, but normalizes cortisol levels in only 25% of patients.[95] The long-acting formulation of pasireotide normalizes cortisol levels in 40% of patients.[96] It causes hyperglycemia in most patients. This is a pituitary-targeted therapy and should be used only in patients with hypercortisolism due to ACTH-secreting pituitary tumors.[100] There is a high risk of hyperglycemia, which requires careful patient selection, and a risk of QTc prolongation.[26]

Dopamine agonist: cabergoline has been used off-label in the treatment of Cushing disease in some countries.[101]

Steroidogenesis inhibitors: osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate decrease adrenal corticosteroid production.[92][93][102] They should only be used by physicians familiar with their use. Osilodrostat is approved in the US and Europe for use in Cushing disease. It is a potent, rapidly active steroid 11-beta-hydroxylase inhibitor and is generally well tolerated.[102] There is a risk of hypocortisolism, hypokalemia, and QTc prolongation; careful monitoring for hyperandrogenism is needed in women.[26] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[103][104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Glucocorticoid receptor antagonist: mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

pasireotide: 0.3 to 0.9 mg subcutaneously twice daily; 10-40 mg intramuscularly every 4 weeks

OR

cabergoline: consult specialist for guidance on dose

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

Secondary options

mitotane: consult specialist for guidance on dose

Tertiary options

etomidate: consult specialist for guidance on dose

Consider – postsurgical corticosteroid replacement therapy

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
Consider – 

postsurgical corticosteroid replacement therapy

Treatment recommended for SOME patients in selected patient group

Patients who undergo pituitary adenomectomy may become temporarily or permanently dependent on physiologic replacement of cortisol. It is necessary to monitor blood pressure, check for orthostatic symptoms, and assess general sense of energy or fatigue.

As postoperative hypocortisolism is predictive of remission, some centers advocate withholding routine corticosteroid therapy after pituitary surgery and monitoring cortisol levels every 8 hours or if symptoms of adrenal insufficiency occur. If adrenal insufficiency occurs or low cortisol levels are documented, corticosteroid therapy should be initiated. Other centers begin routine corticosteroid therapy immediately after surgery and evaluate for remission of hypercortisolism later in the postoperative course.[78] This is done by measuring morning cortisol at least 24 hours after the last dose of corticosteroid therapy. Patients with a postoperative morning cortisol of <2 micrograms/dL are considered to be in remission and can transition into long-term follow-up. Patients with a postoperative morning cortisol of >5 micrograms/dL require further evaluation and possibly further therapy. Patients with a morning cortisol between 2 and 5 micrograms/dL should be followed with additional measurements to detect a drop in subsequent morning cortisol levels. Individuals with morning cortisols >2 micrograms/dL after surgery are 2.5 times more likely to have recurrences than those with cortisol levels <2 micrograms/dL.[74][75][76]

Corticosteroids are usually rapidly tapered to physiologic doses within 1 week or less (often by discharge from the hospital). Testing to see if the hypothalamic-pituitary-adrenal axis (HPA) has recovered can be done in follow-up by 3 months after surgery. Testing is usually a morning cortisol prior to the patient taking the morning hydrocortisone dose, if hydrocortisone therapy had been continued. Cortisol levels of >20 micrograms/dL indicate recovery of the axis. Levels <3 micrograms/dL indicate a continued need for corticosteroids. Levels between 3 micrograms/dL and 20 micrograms/dL should prompt further testing (cosyntropin stimulation testing, insulin tolerance testing, or metyrapone testing). Once recovery of HPA axis has been established, patients need to undergo testing for possible recurrence. Salivary cortisol testing seems to be a better predictor of early recurrence.[76][79]

Primary options

hydrocortisone: 10-25 mg per meter square body surface area/day orally given in 2-3 divided doses; usual dose is a larger dose in the morning (10-15 mg) and a smaller dose in the late afternoon (5-10 mg)

Consider – postsurgical pituitary hormone replacement therapy

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
Consider – 

postsurgical pituitary hormone replacement therapy

Treatment recommended for SOME patients in selected patient group

Any combination of deficiencies may occur.

Levothyroxine is used to achieve a free T4 in the upper half of the normal range. A thyroid-stimulating hormone should not be used to guide therapy.[112]

Testosterone therapy is used to achieve a testosterone level in the normal range.[112]

Women with an intact uterus taking estrogen replacement also need 10 days of progestin each month in addition to estrogen replacement therapy.

Decision to treat with growth hormone should be individualized for each patient based on symptoms, benefits, and risk of therapy.[112] Dose titration should occur every month to achieve clinical response (i.e., energy level, sense of well-being, and lean body mass) and an insulin-like growth factor 1 (IGF-1) level in the age-adjusted mid- to upper-normal range.

Desmopressin is titrated to control symptomatic excessive urine output. This is based on patient preference. Serum sodium and symptoms are monitored periodically to evaluate adequacy of treatment.[112]

Primary options

levothyroxine: 1.8 micrograms/kg/day orally

-- AND / OR --

testosterone transdermal: 2.5 to 7.5 mg once daily, titrate according to response in men

or

testosterone cypionate: 200 mg intramuscularly every 2 weeks, titrate according to response in men

or

estradiol: 2 mg orally once daily in women

or

estrogens, conjugated: 0.625 to 1.25 mg orally once daily in women

and

medroxyprogesterone: 5-10 mg orally once daily on 10 days of each month if woman has intact uterus and on estradiol or estrogen

-- AND / OR --

somatropin (recombinant): dose depends on brand used; consult specialist for guidance on dose

-- AND / OR --

desmopressin: 0.1 mg orally once to three times daily

1st line – medical therapy alone

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
1st line – 

medical therapy alone

Medical treatment alone with a somatostatin analog (pasireotide), a dopamine agonist (cabergoline), a steroidogenesis inhibitor (osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate), or a glucocorticoid receptor antagonist (mifepristone) has been increasingly used in clinical practice. Medical therapy is indicated to control cortisol secretion in patients with mild hypercortisolism or where surgery is declined or not feasible (e.g., high surgical risk, metastatic disease).[91][92][93][94] However, there is a paucity of high-quality studies of medical therapy in Cushing disease, and caution should be employed when comparing efficacy rates owing to the variability in study design and quality.[94]

Somatostatin analog: pasireotide binds to a wide array of somatostatin receptors, with a much greater affinity for somatostatin receptor 5, which is predominantly expressed in corticotroph adenomas. Use of the regular-release formulation of pasireotide decreases cortisol in most patients, but normalizes cortisol levels in only 25% of patients.[95] The long-acting formulation of pasireotide normalizes cortisol levels 40% of patients.[96] It causes hyperglycemia in most patients. This is a pituitary-targeted therapy and should only be used in patients with hypercortisolism due to ACTH-secreting pituitary tumors.[100] There is a high risk of hyperglycemia, which requires careful patient selection, and a risk of QTc prolongation.[26]

Dopamine agonist: cabergoline has been used off-label in the treatment of Cushing disease in some countries.[101]

Steroidogenesis inhibitors: osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate decrease adrenal corticosteroid production.[92][93][102] They should only be used by physicians familiar with their use. Osilodrostat is approved in the US and Europe for use in Cushing disease. It is a potent, rapidly active steroid 11-beta-hydroxylase inhibitor and is generally well tolerated.[102] There is a risk of hypocortisolism, hypokalemia, and QTc prolongation; careful monitoring for hyperandrogenism is needed in women.[26] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[103][104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Glucocorticoid receptor antagonist: mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

pasireotide: 0.3 to 0.9 mg subcutaneously twice daily; 10-40 mg intramuscularly every 4 weeks

OR

cabergoline: consult specialist for guidance on dose

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

Secondary options

mitotane: consult specialist for guidance on dose

Tertiary options

etomidate: consult specialist for guidance on dose

2nd line – repeat transsphenoidal pituitary adenomectomy

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
2nd line – 

repeat transsphenoidal pituitary adenomectomy

In patients who received transsphenoidal pituitary adenomectomy as first-line therapy, additional therapy should be considered in patients with failure of initial pituitary surgery or with recurrence of disease. The incidence of recurrence in Cushing disease is high, with 50% of recurrences occurring during the first 50 months after first surgery.[80] Re-operation is frequently the preferred therapy if initial surgery fails. It should be considered in all patients with recurrence or persistence of disease. It is effective in about two-thirds of patients.[83][84][85] However, the risk of pituitary deficiency after re-operation is 50%. This is significantly higher than after initial surgical therapy.[83]

Patients with mild cortisol excess (biochemical evidence of hypercortisolemia but no clinical signs or symptoms of Cushing syndrome) should have therapy carefully weighed because benefit of surgery has not been convincingly demonstrated.[71]

Consider – medical therapy before surgery

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
Consider – 

medical therapy before surgery

Treatment recommended for SOME patients in selected patient group

A somatostatin analog (pasireotide), a dopamine agonist (cabergoline), a steroidogenesis inhibitor (osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, etomidate), or a glucocorticoid receptor antagonist (mifepristone) is occasionally used for mild hypercortisolism, or short term for severe hypercortisolism, before other therapies are undertaken.[91][92][93][94]

Somatostatin analog: pasireotide binds to a wide array of somatostatin receptors, with a much greater affinity for somatostatin receptor 5, which is predominantly expressed in corticotroph adenomas. Use of the regular-release formulation of pasireotide decreases cortisol in most patients, but normalizes cortisol levels in only 25% of patients.[95] The long-acting formulation of pasireotide normalizes cortisol levels in 40% of patients.[96] It causes hyperglycemia in most patients. This is a pituitary-targeted therapy and should be used only in patients with hypercortisolism due to ACTH-secreting pituitary tumors.[100] There is a high risk of hyperglycemia, which requires careful patient selection, and a risk of QTc prolongation.[26]

Dopamine agonist: cabergoline has been used off-label in the treatment of Cushing disease in some countries.[101]

Steroidogenesis inhibitors: osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate decrease adrenal corticosteroid production.[92][93][102] They should only be used by physicians familiar with their use. Osilodrostat is approved in the US and Europe for use in Cushing disease. It is a potent, rapidly active steroid 11-beta-hydroxylase inhibitor and is generally well tolerated.[102] There is a risk of hypocortisolism, hypokalemia, and QTc prolongation; careful monitoring for hyperandrogenism is needed in women.[26] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[103][104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Glucocorticoid receptor antagonist: mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

pasireotide: 0.3 to 0.9 mg subcutaneously twice daily; 10-40 mg intramuscularly every 4 weeks

OR

cabergoline: consult specialist for guidance on dose

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

Secondary options

mitotane: consult specialist for guidance on dose

Tertiary options

etomidate: consult specialist for guidance on dose

Consider – postsurgical corticosteroid replacement therapy

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
Consider – 

postsurgical corticosteroid replacement therapy

Treatment recommended for SOME patients in selected patient group

Patients who undergo pituitary adenomectomy may become temporarily or permanently dependent on physiologic replacement of cortisol. It is necessary to monitor blood pressure, check for orthostatic symptoms, and assess general sense of energy or fatigue.

As postoperative hypocortisolism is predictive of remission, some centers advocate withholding routine corticosteroid therapy after pituitary surgery and monitoring cortisol levels every 8 hours or if symptoms of adrenal insufficiency occur. If adrenal insufficiency occurs or low cortisol levels are documented, corticosteroid therapy should be initiated. Other centers begin routine corticosteroid therapy immediately after surgery and evaluate for remission of hypercortisolism later in the postoperative course.[78] This is done by measuring morning cortisol at least 24 hours after the last dose of corticosteroid therapy. Patients with a postoperative morning cortisol of <2 micrograms/dL are considered to be in remission and can transition into long-term follow-up. Patients with a postoperative morning cortisol of >5 micrograms/dL require further evaluation and possibly further therapy. Patients with a morning cortisol between 2 and 5 micrograms/dL should be followed with additional measurements to detect a drop in subsequent morning cortisol levels. Individuals with morning cortisols >2 micrograms/dL after surgery are 2.5 times more likely to have recurrences than those with cortisol levels <2 micrograms/dL.[74][75][76]

Corticosteroids are usually rapidly tapered to physiologic doses within 1 week or less (often by discharge from the hospital). Testing to see if the hypothalamic-pituitary-adrenal (HPA) axis has recovered can be done in follow-up by 3 months after surgery. Testing is usually a morning cortisol prior to the patient taking the morning hydrocortisone dose, if hydrocortisone therapy had been continued. Cortisol levels of >20 micrograms/dL indicate recovery of the axis. Levels <3 micrograms/dL indicate a continued need for corticosteroids. Levels between 3 micrograms/dL and 20 micrograms/dL should prompt further testing (cosyntropin stimulation testing, insulin tolerance testing, or metyrapone testing). Once recovery of HPA axis has been established, patients need to undergo testing for possible recurrence. Salivary cortisol testing seems to be a better predictor of early recurrence.[76][79]

Primary options

hydrocortisone: 10-25 mg per meter square body surface area/day orally given in 2-3 divided doses; usual dose is a larger dose in the morning (10-15 mg) and a smaller dose in the late afternoon (5-10 mg)

Consider – postsurgical pituitary hormone replacement therapy

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
Consider – 

postsurgical pituitary hormone replacement therapy

Treatment recommended for SOME patients in selected patient group

Any combination of deficiencies may occur. The risk of pituitary deficiency after reoperation is 50%. This is significantly higher than after initial surgical therapy.[83]

Levothyroxine is used to achieve a free T4 in the upper half of the normal range. A thyroid-stimulating hormone should not be used to guide therapy.[112]

Testosterone therapy is used to achieve a testosterone level in the normal range.[112]

Women with an intact uterus taking estrogen replacement also need 10 days of progestin each month in addition to estrogen replacement therapy.

Decision to treat with growth hormone should be individualized for each patient based on symptoms, benefits, and risk of therapy.[112] Dose titration should occur every month to achieve clinical response (i.e., energy level, sense of well-being, and lean body mass) and an insulin-like growth factor 1 (IGF-1) level in the age-adjusted mid- to upper-normal range.

Desmopressin is titrated to control symptomatic excessive urine output. This is based on patient preference. Serum sodium and symptoms are monitored periodically to evaluate adequacy of treatment.[112]

Primary options

levothyroxine: 1.8 micrograms/kg/day orally

-- AND / OR --

testosterone transdermal: 2.5 to 7.5 mg once daily, titrate according to response in men

or

testosterone cypionate: 200 mg intramuscularly every 2 weeks, titrate according to response in men

or

estradiol: 2 mg orally once daily in women

or

estrogens, conjugated: 0.625 to 1.25 mg orally once daily in women

and

medroxyprogesterone: 5-10 mg orally once daily on 10 days of each month if woman has intact uterus and on estradiol or estrogen

-- AND / OR --

somatropin (recombinant): dose depends on brand used; consult specialist for guidance on dose

-- AND / OR --

desmopressin: 0.1 mg orally once to three times daily

2nd line – medical therapy alone

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
2nd line – 

medical therapy alone

In patients who received transsphenoidal pituitary adenomectomy as first-line therapy, additional therapy should be considered in patients with failure of initial pituitary surgery or with recurrence of disease. The incidence of recurrence in Cushing disease is high, with 50% of recurrences occurring during the first 50 months after first surgery.[80] Standard therapies include repeat pituitary surgery, radiation therapy, bilateral adrenalectomy, or medical therapy.[72][81]

Success rates of these treatment options vary between 25% (for some of the medical therapies) and 100% (bilateral adrenalectomy). Treatment options have specific advantages, limitations, and side-effects so treatment decisions should be individualized according to the specific needs of the patient and risk of complications.[80][82]

Medical treatment has been increasingly used in clinical practice and is indicated to control cortisol secretion in cases with persistent or recurrent hypercortisolism after surgery, or where surgery is declined or not feasible (e.g., high surgical risk, metastatic disease).[91][92][93][94]

Somatostatin analog: pasireotide binds to a wide array of somatostatin receptors, with a much greater affinity for somatostatin receptor 5, which is predominantly expressed in corticotroph adenomas. Use of the regular-release formulation of pasireotide decreases cortisol in most patients, but normalizes cortisol levels in only 25% of patients.[95] The long-acting formulation of pasireotide normalizes cortisol levels in 40% of patients.[96] It causes hyperglycemia in most patients. This is a pituitary-targeted therapy and should be used only in patients with hypercortisolism due to ACTH-secreting pituitary tumors.[100] There is a high risk of hyperglycemia, which requires careful patient selection, and a risk of QTc prolongation.[26]

Dopamine agonist: cabergoline has been used off-label in the treatment of Cushing disease in some countries.[101]

Steroidogenesis inhibitors: osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate decrease adrenal corticosteroid production and can be used (though off-label in most countries) in the treatment of Cushing syndrome. They should only be used by physicians familiar with their use. Osilodrostat is approved in the US and Europe for use in Cushing disease. It is a potent, rapidly active steroid 11-beta-hydroxylase inhibitor and is generally well tolerated.[102] There is a risk of hypocortisolism, hypokalemia, and QTc prolongation; careful monitoring for hyperandrogenism is needed in women.[26] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[103][104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Glucocorticoid receptor antagonist: mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

pasireotide: 0.3 to 0.9 mg subcutaneously twice daily; 10-40 mg intramuscularly every 4 weeks

OR

cabergoline: consult specialist for guidance on dose

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

Secondary options

mitotane: consult specialist for guidance on dose

Tertiary options

etomidate: consult specialist for guidance on dose

2nd line – pituitary radiation therapy

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
2nd line – 

pituitary radiation therapy

Radiation therapy by conventional fractionated radiation therapy or stereotactic radiosurgery is most commonly used in patients with persistent hypercortisolism after incomplete corticotroph tumor resection, particularly if the tumor is aggressive or invasive or considered unresectable.[26] This modality is perhaps best used as part of the therapy for patients with mild residual hypercortisolism, as full effects of therapy can take several years to be realized. Radiation of tumors located close to the optic chiasm increases the risk of damage to the optic chiasm, and this risk should be considered prior to therapy.

After 3 to 5 years, both traditional fractionated radiation therapy and stereotactic radiosurgery attain remission in 50% to 60% of patients.[86][87][88]

Insufficient data exist to estimate the long-term recurrence rates after therapy.

Traditional fractionated radiation therapy and stereotactic radiosurgery have similar rates of post-therapy hypopituitarism.

Consider – medical therapy before radiation therapy

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
Consider – 

medical therapy before radiation therapy

Treatment recommended for SOME patients in selected patient group

A somatostatin analog (pasireotide), a dopamine agonist (cabergoline), a steroidogenesis inhibitor (osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, etomidate), or a glucocorticoid receptor antagonist (mifepristone) is occasionally used short term for severe hypercortisolism, before other therapies are undertaken.[91][92][93][94]

Somatostatin analog: pasireotide binds to a wide array of somatostatin receptors, with a much greater affinity for somatostatin receptor 5, which is predominantly expressed in corticotroph adenomas. Use of the regular-release formulation of pasireotide decreases cortisol in most patients, but normalizes cortisol levels in only 25% of patients.[95] The long-acting formulation of pasireotide normalizes cortisol levels in 40% of patients.[96] It causes hyperglycemia in most patients. This is a pituitary-targeted therapy and should be used only in patients with hypercortisolism due to ACTH-secreting pituitary tumors.[100] There is a high risk of hyperglycemia, which requires careful patient selection, and a risk of QTc prolongation.[26]

Dopamine agonist: cabergoline has been used off-label in the treatment of Cushing disease in some countries.[101]

Steroidogenesis inhibitors: osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate decrease adrenal corticosteroid production.[92][93][102] They should only be used by physicians familiar with their use. Osilodrostat is approved in the US and Europe for use in Cushing disease. It is a potent, rapidly active steroid 11-beta-hydroxylase inhibitor and is generally well tolerated.[102] There is a risk of hypocortisolism, hypokalemia, and QTc prolongation; careful monitoring for hyperandrogenism is needed in women.[26] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[103][104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Glucocorticoid receptor antagonist: mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

pasireotide: 0.3 to 0.9 mg subcutaneously twice daily; 10-40 mg intramuscularly every 4 weeks

OR

cabergoline: consult specialist for guidance on dose

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

Secondary options

mitotane: consult specialist for guidance on dose

Tertiary options

etomidate: consult specialist for guidance on dose

Consider – post-radiation corticosteroid replacement therapy

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
Consider – 

post-radiation corticosteroid replacement therapy

Treatment recommended for SOME patients in selected patient group

Patients who undergo pituitary irradiation may become temporarily or permanently dependent on physiologic replacement of cortisol. This may occur even years after therapy. Consequently, it is necessary to monitor for adrenal insufficiency for years after radiation therapy (e.g., monitor blood pressure, check for orthostatic symptoms, and assess general sense of energy or fatigue).

Slow taper of corticosteroid replacement may be done over time if the pituitary axis recovers.

Primary options

hydrocortisone: 10-25 mg per meter square body surface area/day orally given in 2-3 divided doses; usual dose is a larger dose in the morning (10-15 mg) and a smaller dose in the late afternoon (5-10 mg)

Consider – post-radiation pituitary hormone replacement therapy

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
Consider – 

post-radiation pituitary hormone replacement therapy

Treatment recommended for SOME patients in selected patient group

Any combination of deficiencies may occur.

Levothyroxine is used to achieve a free T4 in the upper half of the normal range. TSH should not be used to guide therapy.[112]

Testosterone therapy is used to achieve a testosterone level in the normal range.[112]

Women with an intact uterus taking estrogen replacement also need 10 days of progestin each month in addition to estrogen replacement therapy.

Decision to treat with growth hormone should be individualized for each patient based on symptoms, benefits, and risk of therapy.[112] Dose titration should occur every month to achieve clinical response (i.e., energy level, sense of well-being, and lean body mass) and an insulin-like growth factor 1 (IGF-1) level in the age-adjusted mid- to upper-normal range.

Desmopressin is titrated to control symptomatic excessive urine output. This is based on patient preference. Serum sodium and symptoms are monitored periodically to evaluate adequacy of treatment.[112]

Primary options

levothyroxine: 1.8 micrograms/kg/day orally

-- AND / OR --

testosterone transdermal: 2.5 to 7.5 mg once daily, titrate according to response in men

or

testosterone cypionate: 200 mg intramuscularly every 2 weeks, titrate according to response in men

or

estradiol: 2 mg orally once daily in women

or

estrogens, conjugated: 0.625 to 1.25 mg orally once daily in women

and

medroxyprogesterone: 5-10 mg orally once daily on 10 days of each month if woman has intact uterus and on estradiol or estrogen

-- AND / OR --

somatropin (recombinant): dose depends on brand used; consult specialist for guidance on dose

-- AND / OR --

desmopressin: 0.1 mg orally once to three times daily

2nd line – bilateral adrenalectomy

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
2nd line – 

bilateral adrenalectomy

Additional therapy should be considered in patients with failure of initial pituitary surgery or with recurrence of disease. The incidence of recurrence in Cushing disease is high, with 50% of recurrences occurring during the first 50 months after first surgery.[80] Standard therapies include repeat pituitary surgery, radiation therapy, bilateral adrenalectomy, or medical therapy.[72][81]

Success rates of these treatment options vary between 25% (for some of the medical therapies) and 100% (bilateral adrenalectomy). Treatment options have specific advantages, limitations, and side-effects so treatment decisions should be individualized according to the specific needs of the patient and risk of complications.[80][82]

Bilateral adrenalectomy should be considered in patients with severe hypercortisolism following ineffective reoperation, or if a patient is not a candidate for reoperation, depending on patient preference and risk of complications.

Provides cure for all endogenous hypercortisolism. A meta-analysis of 37 studies (1320 patients, 82% with Cushing disease, 13% with ectopic Cushing syndrome, and 5% with primary adrenal hyperplasia) showed that bilateral adrenalectomy is relatively safe and provides adequate success.[111] Although residual cortisol secretion due to accessory adrenal tissue or adrenal remnants was found in 3% to 34%, less than 2% had a relapse of Cushing syndrome. Symptoms of hypercortisolism (e.g., hypertension, obesity, or depression) improved in the majority of the patients after bilateral adrenalectomy (7 studies, 195 patients).

Creates adrenal insufficiency with the need for lifelong corticosteroid replacement.

Increases the risk of Nelson syndrome, which is progression of the ACTH-secreting pituitary adenoma. This progression can cause hyperpigmentation from excessive ACTH and intracranial compressive symptoms from growth of the tumor outside the sella.

Newer laparoscopic methods of adrenalectomy allow for more rapid recovery and tolerability.

Plus – permanent postsurgical corticosteroid and mineralocorticoid replacement therapy

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
Plus – 

permanent postsurgical corticosteroid and mineralocorticoid replacement therapy

Treatment recommended for ALL patients in selected patient group

It is necessary to monitor blood pressure, check for orthostatic symptoms, and assess general sense of energy or fatigue at regular intervals.

Replacement glucocorticoids and mineralocorticoids are necessary in patients who undergo bilateral adrenalectomy.

Primary options

hydrocortisone: 10-25 mg per meter square body surface area/day orally given in 2-3 divided doses; usual dose is a larger dose in the morning (10-15 mg) and a smaller dose in the late afternoon (5-10 mg)

and

fludrocortisone: 0.05 to 0.1 mg orally once daily

Consider – medical therapy before surgery

Back
ONGOING
|
Cushing disease (adrenocorticotropic hormone [ACTH]-secreting pituitary tumor)
Consider – 

medical therapy before surgery

Treatment recommended for SOME patients in selected patient group

A somatostatin analog (pasireotide), a dopamine agonist (cabergoline), a steroidogenesis inhibitor (osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, etomidate), or a glucocorticoid receptor antagonist (mifepristone) is occasionally used short term for severe hypercortisolism, before other therapies are undertaken.[91][92][93][94]

Somatostatin analog: pasireotide binds to a wide array of somatostatin receptors, with a much greater affinity for somatostatin receptor 5, which is predominantly expressed in corticotroph adenomas. Use of the regular-release formulation of pasireotide decreases cortisol in most patients, but normalizes cortisol levels in only 25% of patients.[95] The long-acting formulation of pasireotide normalizes cortisol levels in 40% of patients.[96] It causes hyperglycemia in most patients. This is a pituitary-targeted therapy and should be used only in patients with hypercortisolism due to ACTH-secreting pituitary tumors.[100] There is a high risk of hyperglycemia, which requires careful patient selection, and a risk of QTc prolongation.[26]

Dopamine agonist: cabergoline has been used off-label in the treatment of Cushing disease in some countries.[101]

Steroidogenesis inhibitors: osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate decrease adrenal corticosteroid production.[92][93][102] They should only be used by physicians familiar with their use. Osilodrostat is approved in the US and Europe for use in Cushing disease. It is a potent, rapidly active steroid 11-beta-hydroxylase inhibitor and is generally well tolerated.[102] There is a risk of hypocortisolism, hypokalemia, and QTc prolongation; careful monitoring for hyperandrogenism is needed in women.[26] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[103][104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Glucocorticoid receptor antagonist: mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

pasireotide: 0.3 to 0.9 mg subcutaneously twice daily; 10-40 mg intramuscularly every 4 weeks

OR

cabergoline: consult specialist for guidance on dose

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

Secondary options

mitotane: consult specialist for guidance on dose

Tertiary options

etomidate: consult specialist for guidance on dose

ectopic ACTH or corticotropin-releasing hormone (CRH) syndrome

1st line – surgical resection or ablation of tumor and metastases

Back
ONGOING
|
ectopic ACTH or corticotropin-releasing hormone (CRH) syndrome
1st line – 

surgical resection or ablation of tumor and metastases

Resection or ablation of ectopic tumors producing ACTH or CRH is the preferred mode of therapy. Many cases have severe hypercortisolism requiring steroidogenesis inhibition therapy in addition to surgery.

Consider – medical therapy before surgery

Back
ONGOING
|
ectopic ACTH or corticotropin-releasing hormone (CRH) syndrome
Consider – 

medical therapy before surgery

Treatment recommended for SOME patients in selected patient group

Patients with ectopic ACTH-producing tumors may have extremely severe hypercortisolism, and require reduction in cortisol before proceeding to surgery. In these cases, steroidogenesis inhibitor therapy (ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane, etomidate) or a glucocorticoid receptor antagonist (mifepristone) can be used to block cortisol action or lower cortisol levels in preparation before surgery.[93]

These agents should only be used by physicians familiar with their use. Osilodrostat is a potent oral inhibitor of steroidogenesis (inhibits steroid 11-beta-hydroxylase) that is approved in the US for the treatment of Cushing disease in patients where pituitary surgery is not an option or has not been curative, and in Europe and Japan for the treatment of endogenous Cushing syndrome.[26][102] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

Secondary options

mitotane: consult specialist for guidance on dose

Tertiary options

etomidate: consult specialist for guidance on dose

Consider – chemotherapy or radiation therapy for primary tumor

Back
ONGOING
|
ectopic ACTH or corticotropin-releasing hormone (CRH) syndrome
Consider – 

chemotherapy or radiation therapy for primary tumor

Treatment recommended for SOME patients in selected patient group

Depending upon the tumor source of the ectopic ACTH or CRH syndrome, adjunctive chemotherapy and/or radiation therapy may be indicated.

See local specialist protocol for dosing guidelines.

2nd line – bilateral adrenalectomy

Back
ONGOING
|
ectopic ACTH or corticotropin-releasing hormone (CRH) syndrome
2nd line – 

bilateral adrenalectomy

Should be considered if surgical resection is not possible, depending on patient preference and risk of complications.

Provides cure for all endogenous hypercortisolism.

Creates adrenal insufficiency with the need for lifelong corticosteroid replacement.

Plus – permanent postsurgical corticosteroid and mineralocorticoid replacement therapy

Back
ONGOING
|
ectopic ACTH or corticotropin-releasing hormone (CRH) syndrome
Plus – 

permanent postsurgical corticosteroid and mineralocorticoid replacement therapy

Treatment recommended for ALL patients in selected patient group

It is necessary to monitor blood pressure, check for orthostatic symptoms, and assess general sense of energy or fatigue.

Replacement glucocorticoids and mineralocorticoids are necessary in patients who undergo bilateral adrenalectomy.

Primary options

hydrocortisone: 10-25 mg per meter square body surface area/day orally given in 2-3 divided doses; usual dose is a larger dose in the morning (10-15 mg) and a smaller dose in the late afternoon (5-10 mg)

and

fludrocortisone: 0.05 to 0.1 mg orally once daily

Consider – medical therapy before surgery

Back
ONGOING
|
ectopic ACTH or corticotropin-releasing hormone (CRH) syndrome
Consider – 

medical therapy before surgery

Treatment recommended for SOME patients in selected patient group

Patients with ectopic ACTH-producing tumors may have extremely severe hypercortisolism, and require reduction in cortisol before proceeding to surgery. In these cases, steroidogenesis inhibitor therapy (ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane, etomidate) or a glucocorticoid receptor antagonist (mifepristone) can be used to block cortisol action or lower cortisol levels in preparation before surgery.[93]

These agents should only be used by physicians familiar with their use. Osilodrostat is a potent oral inhibitor of steroidogenesis (inhibits steroid 11-beta-hydroxylase) that is approved in the US for the treatment of Cushing disease in patients where pituitary surgery is not an option or has not been curative, and in Europe and Japan for the treatment of endogenous Cushing syndrome.[26][102] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

Secondary options

mitotane: consult specialist for guidance on dose

Tertiary options

etomidate: consult specialist for guidance on dose

Consider – chemotherapy or radiation therapy for primary tumor

Back
ONGOING
|
ectopic ACTH or corticotropin-releasing hormone (CRH) syndrome
Consider – 

chemotherapy or radiation therapy for primary tumor

Treatment recommended for SOME patients in selected patient group

Depending upon the tumor source of the ectopic ACTH or CRH syndrome, adjunctive chemotherapy and/or radiation therapy may be indicated.

See local specialist protocol for dosing guidelines.

3rd line – medical therapy only

Back
ONGOING
|
ectopic ACTH or corticotropin-releasing hormone (CRH) syndrome
3rd line – 

medical therapy only

There is a paucity of high-quality studies of medical therapy in Cushing syndrome.[94] The decision about which therapy to use should be individualized for each patient, factoring patient preference and risk of complications into any decision.[93]

Steroidogenesis inhibitors: ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane, and etomidate decrease adrenal corticosteroid production and can be used (though off-label in most countries) in the treatment of Cushing syndrome.[93] These agents should only be used by physicians familiar with their use. Osilodrostat is a potent oral inhibitor of steroidogenesis (inhibits steroid 11-beta-hydroxylase) that is approved in the US for the treatment of Cushing disease in patients where pituitary surgery is not an option or has not been curative, and in Europe and Japan for the treatment of endogenous Cushing syndrome.[26][102] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Glucocorticoid receptor antagonist: mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

Secondary options

mitotane: consult specialist for guidance on dose

Tertiary options

etomidate: consult specialist for guidance on dose

Consider – chemotherapy or radiation therapy for primary tumor

Back
ONGOING
|
ectopic ACTH or corticotropin-releasing hormone (CRH) syndrome
Consider – 

chemotherapy or radiation therapy for primary tumor

Treatment recommended for SOME patients in selected patient group

Depending upon the tumor source of the ectopic ACTH or CRH syndrome, adjunctive chemotherapy and/or radiation therapy may be indicated.

See local specialist protocol for dosing guidelines.

ACTH-independent due to unilateral adrenal carcinoma or adenoma

1st line – unilateral adrenalectomy or tumor resection

Back
ONGOING
|
ACTH-independent due to unilateral adrenal carcinoma or adenoma
1st line – 

unilateral adrenalectomy or tumor resection

Preferred method of therapy in patients with unilateral cortisol-secreting adrenal adenoma. Laparoscopic adrenalectomy is the preferred method in most cases. Complete resection of the adrenal gland cures hypercortisolism in all patients without high risk of long-term adrenal insufficiency. Adrenalectomy has a beneficial effect on cardiovascular risk factors in patients with subclinical Cushing syndrome overall and compared with conservative management.[113]

Patients with mild cortisol excess (biochemical evidence of hypercortisolemia but no clinical signs or symptoms of Cushing syndrome) should have therapy carefully weighed because benefit of surgery has not been demonstrated.[52][53]

Adrenal carcinoma is extremely rare. First-line therapy in many patients is surgical resection of tumor; however, at the time of diagnosis the disease has often progressed beyond the point where surgical therapy is effective. The effectiveness of chemotherapy and adjunctive therapies in both early- and late-stage disease has shown mixed results in clinical trials; however, patients should be considered for treatment with mitotane and enrollment in clinical trials (if available).[10]

Consider – medical therapy before surgery

Back
ONGOING
|
ACTH-independent due to unilateral adrenal carcinoma or adenoma
Consider – 

medical therapy before surgery

Treatment recommended for SOME patients in selected patient group

Steroidogenesis inhibitors: ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane, and etomidate decrease adrenal corticosteroid production. They are generally used short term for severe hypercortisolism, before other therapies are undertaken.[93] These agents should only be used by physicians familiar with their use. Osilodrostat is a potent oral inhibitor of steroidogenesis (inhibits steroid 11-beta-hydroxylase) that is approved in the US for the treatment of Cushing disease in patients where pituitary surgery is not an option or has not been curative, and in Europe and Japan for the treatment of endogenous Cushing syndrome.[26][102] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Glucocorticoid receptor antagonist: mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

OR

mitotane: consult specialist for guidance on dose

Secondary options

etomidate: consult specialist for guidance on dose

Consider – chemotherapy or radiation therapy for adrenal carcinoma

Back
ONGOING
|
ACTH-independent due to unilateral adrenal carcinoma or adenoma
Consider – 

chemotherapy or radiation therapy for adrenal carcinoma

Treatment recommended for SOME patients in selected patient group

Depending upon the stage of adrenal carcinoma, adjunctive chemotherapy and/or radiation therapy may be indicated.

See local specialist protocol for dosing guidelines.

2nd line – medical therapy only

Back
ONGOING
|
ACTH-independent due to unilateral adrenal carcinoma or adenoma
2nd line – 

medical therapy only

Steroidogenesis inhibitors: osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate decrease adrenal corticosteroid production and can be used (though off-label in most countries) in the treatment of Cushing syndrome.[93] These agents should only be used by physicians familiar with their use. Osilodrostat is a potent oral inhibitor of steroidogenesis (inhibits steroid 11-beta-hydroxylase) that is approved in the US for the treatment of Cushing disease in patients where pituitary surgery is not an option or has not been curative, and in Europe and Japan for the treatment of endogenous Cushing syndrome.[26][102] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[103][104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Glucocorticoid receptor antagonist: mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

OR

mitotane: consult specialist for guidance on dose

Secondary options

etomidate: consult specialist for guidance on dose

Consider – chemotherapy or radiation therapy for adrenal carcinoma

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ONGOING
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ACTH-independent due to unilateral adrenal carcinoma or adenoma
Consider – 

chemotherapy or radiation therapy for adrenal carcinoma

Treatment recommended for SOME patients in selected patient group

Depending upon the stage of adrenal carcinoma, adjunctive chemotherapy and/or radiation therapy may be indicated.

See local specialist protocol for dosing guidelines.

ACTH-independent due to bilateral adrenal disease (hyperplasia or adenoma)

1st line – bilateral adrenalectomy

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ONGOING
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ACTH-independent due to bilateral adrenal disease (hyperplasia or adenoma)
1st line – 

bilateral adrenalectomy

First-line therapy in patients with bilateral adrenal disease from autonomous nodule formation or bilateral hyperplasia.

Provides cure for all endogenous hypercortisolism. Creates adrenal insufficiency with the need for lifelong corticosteroid replacement.

Plus – permanent postsurgical corticosteroid and mineralocorticoid replacement therapy

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ONGOING
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ACTH-independent due to bilateral adrenal disease (hyperplasia or adenoma)
Plus – 

permanent postsurgical corticosteroid and mineralocorticoid replacement therapy

Treatment recommended for ALL patients in selected patient group

It is necessary to monitor blood pressure, check for orthostatic symptoms, and assess general sense of energy or fatigue.

Replacement glucocorticoids and mineralocorticoids are necessary in patients who undergo bilateral adrenalectomy.

Primary options

hydrocortisone: 10-25 mg per meter square body surface area/day orally given in 2-3 divided doses; usual dose is a larger dose in the morning (10-15 mg) and a smaller dose in the late afternoon (5-10 mg)

and

fludrocortisone: 0.05 to 0.1 mg orally once daily

Consider – medical therapy before surgery

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ONGOING
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ACTH-independent due to bilateral adrenal disease (hyperplasia or adenoma)
Consider – 

medical therapy before surgery

Treatment recommended for SOME patients in selected patient group

Steroidogenesis inhibitors: osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate decrease adrenal corticosteroid production. They are generally used short term for severe hypercortisolism, before other therapies are undertaken.[93] These agents should only be used by physicians familiar with their use. Osilodrostat is a potent oral inhibitor of steroidogenesis (inhibits steroid 11-beta-hydroxylase) that is approved in the US for the treatment of Cushing disease in patients where pituitary surgery is not an option or has not been curative, and in Europe and Japan for the treatment of endogenous Cushing syndrome.[26][102] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[72]

Glucocorticoid receptor antagonist: mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

Secondary options

mitotane: consult specialist for guidance on dose

Tertiary options

etomidate: consult specialist for guidance on dose

2nd line – medical therapy only

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ONGOING
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ACTH-independent due to bilateral adrenal disease (hyperplasia or adenoma)
2nd line – 

medical therapy only

Steroidogenesis inhibitors: osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate decrease adrenal corticosteroid production and can be used (though off-label in most countries) in the treatment of Cushing syndrome.[93] These agents should only be used by physicians familiar with their use. Osilodrostat is a potent oral inhibitor of steroidogenesis (inhibits steroid 11-beta-hydroxylase) that is approved in the US for the treatment of Cushing disease in patients where pituitary surgery is not an option or has not been curative, and in Europe and Japan for the treatment of endogenous Cushing syndrome.[26][102] Ketoconazole and metyrapone have a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] In the US, metyrapone is available for compassionate use. Mitotane has slow onset of action and a narrow therapeutic window. It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma. Etomidate is rarely used and is reserved for emergency situations only. It has rapid onset but must be given intravenously.[93]

Glucocorticoid receptor antagonist: mifepristone blocks cortisol at the receptor level and attenuates the clinical and biochemical effects associated with elevation of cortisol. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome. It may be used for all forms of Cushing syndrome. Cortisol levels may increase during therapy with mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Patients should be monitored for development of adrenal insufficiency.

Dose adjustment should be based on clinical symptoms, biochemical normalization of 24-hour urinary free cortisol, and late-night salivary cortisol (with the exception of mifepristone, where use of cortisol as a marker will not be reliable).

Primary options

osilodrostat: 2 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day

OR

mifepristone: 300 mg orally once daily initially, increase gradually according to response, maximum 1200 mg/day

OR

ketoconazole: 200-600 mg/day orally given in 2-3 divided doses initially, increase gradually according to response, maximum 1600 mg/day given in 2-4 divided doses

OR

levoketoconazole: 150 mg orally twice daily initially, increase gradually according to response, maximum 1200 mg/day

OR

metyrapone: 0.5 to 1 g/day orally given in 3-4 divided doses initially, increase gradually according to response, maximum 6 g/day

Secondary options

mitotane: consult specialist for guidance on dose

Tertiary options

etomidate: consult specialist for guidance on dose

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